REVIEW ARTICLE

INTERNATIONAL JOURNAL OF LABORATO RY HEMATO LOGY

Oral cobalamin (vitamin B12) treatment. An update

` E. ANDRE S*, N. DALI-YOUCEF , T. VOGEL , K. SERRAJ*, J. ZIMMER

*Department of Internal Medicine, Diabetes and Metabolic Diseases, pitaux Universitaires de Ho Strasbourg, Strasbourg, France Laboratory of general and pitaux specialized biochemistry, Ho Universitaires de Strasbourg and Department of Biochemistry, Faculty of Medicine, Strasbourg, France Department of Internal Medicine pitaux and Geriatrics, Ho Universitaires de Strasbourg, Strasbourg, France ne Laboratoire dImmunoge tiqueAllergologie, Centre de Recherche ) Public de la Sante (CRP-Sante de Luxembourg, Luxembourg Correspondence: `s, deProf. E. Andre Service de Me `te cine Interne, Diabe et Maladies taboliques, Clinique Me dicale B, Me pital Civil Hopitaux Universitaires Ho pital, de Strasbourg, 1 porte de lHo 67091 Strasbourg Cedex, France. Tel.: 3 33 88 11 50 66; Fax: 3 33 88 11 62 62; E-mail: emmanuel. andres@chru-strasbourg.fr
doi:10.1111/j.1751-553X.2008.01115.x

SUMMARY

The objective of this review was to evaluate oral cobalamin (vitamin B12) therapy in adult and elderly patients, from the perspective of a hematologist. PubMed was systematically searched for English and French articles published from January 1990 to January 2007. Data from our working group, the Groupe detude des carences en vitamine B12 des Hopitaux Universitaires de Strasbourg, have also been included. Several prospective studies in well-determined population (n = 4), prospective randomized studies (n = 3) and a systematic review by the Cochrane group (n = 1) provide evidence that oral cobalamin therapy may adequately treat cobalamin deciency, particularly hematological abnormalities or manifestations. These studies suggest that at least 1000 lg/day of oral cyanocobalmin are needed for pernicious anemia and a mean daily dose of 250 lg for food-cobalamin malabsorption. This present review conrms the previously reported efcacy of oral cobalamin treatment in adult and elderly patients.

Received 18 February 2008; accepted for publication 30 September 2008 Keywords Cobalamin, vitamin B12, treatment, pernicious anemia, food-cobalamin therapy

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ORAL COBALAMIN THERAPY IN ADULT AND ELDERLY PATIENTS

INTRODUCTION
Cobalamin (vitamin B12) deciency is particularly common in elderly patients (>65 years of age), but is often unrecognized because its clinical manifestations are subtle; however, they are also potentially serious, particularly from a neuropsychiatric and hematologi` cal perspective (Andres et al., 2004). In these patients, the main causes of cobalamin deciency are pernicious anemia and food-cobalamin malabsorption ` (Andres, Goichot & Schlienger, 2000). Management of cobalamin deciency with cobalamin injections is currently well described, but new routes of cobalamin administration (oral and nasal) are being studied (Elia, 1998; Lane & Rojas-Fernandez, 2002). This review summarizes the current knowledge on oral cobalamin curative treatment, from the perspective of a hematologist.

` (Andres et al., 2004). The dietary vitamin B12 enters the digestive tract bound to proteins, known as sali vary R-binders (haptocorrine) (Nicolas & Gueant, ` 1994; Andres et al., 2004). Stomach proteolysis of these proteins requires an acidic pH, but also proper pancreatic release of proteolytic enzymes referred to as pepsin. Free vitamin B12 then attaches to gastric intrinsic factor (IF), which is generated by gastric parietal cells in response to histamine, gastrin and pentagastrin, as well as the presence of food. The generation of vitamin B12IF complex will allow vitamin absorption and it protection from catabolism by intestinal bacteria. The conjugated vitamin B12IF complex is then normally absorbed by the terminal ileum of the small bowel. The complex is then recognized by specialized ileal endocytic receptors (e.g. cubilin) and transported into the portal circulation. Subsequently, cobalamin is transferred to transcobalamin II, the vitamin B12 plasma carrier.

REVIEW CRITERIA
PubMed was systematically searched for articles published from January 1990 to January 2007, using the following expressions: oral cobalamin treatment or oral cobalamin therapy. Articles were restricted to those containing human data that were published in English and French languages. Unpublished data from our working group, the Groupe detude des carences en vitamine B12 des Hopitaux Universitaires de Strasbourg, have also been included.

HEMATOLOGICAL MANIFESTATIONS OF COBALAMIN DEFICIENCY

Hematological abnormalities and manifestations related to cobalamin deciency are highly variable and range from milder conditions such as mild anemia, isolated macrocytosis and hypersegmentation of neutrophils, to severe disorders, including life-threatening anemia, hemolytic anemia and pancytopenia ` (Stabler et al., 1990; Andres et al., 2007). We have previously reported the hematological manifestations or abnormalities (Table 2) in 201 patients (median age 67 6 years) with well-documented cobalamin deciency (mean serum vitamin B12 levels 125 47 pg/ml) extracted from an observational ` cohort study (19952003) (Andres et al., 2006). Hematological abnormalities were reported in at least two-third of the patients: anemia (37%), leukopenia (13.9%), thrombopenia (9.9%), macrocytosis (54%) and hypegmented neutrophils (32%). The mean hemoglobin (Hb) level was 10.3 0.4 g/dl and the mean erythrocyte cell volume was 98.9 25.6 . About 10% of the patients displayed life-threatening hematological manifestations with documented symptomatic pancytopenia (5%), pseudo thrombotic microangiopathy (Moschkowitz) (2.5%), severe anemia (dened as Hb levels <6 g/dl) (2.5%) and hemolytic anemia (1.5%).
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METABOLISM OF COBALAMIN
A typical Western diet contributes 330 lg of cobalamin per day towards the recommended dietary allowance of 2.4 lg/day for adults according to the Food and Nutrition Board of the Institute of Medicine (US) ` (Andres et al., 2008). Vitamin B12 metabolism is complex (Figure 1) and is made up of many processes, defects in any one of which can lead to cobalamin deciency (Nicolas & Gueant, 1994). The total amount of cobalamin stored in body is about 20005000 lg in adults. Around, 80% of this quantity is stored in the liver. Approximately 0.1% of this cobalamin reserve is lost per day by secretions into the gut knowing that not all these secretions are reabsorbed. The different stages of cobalamin metabolism and corresponding causes of cobalamin deciency are shown in Table 1

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ORAL COBALAMIN THERAPY IN ADULT AND ELDERLY PATIENTS 3

Figure 1. Metabolism of vitamin B12. The metabolic journey of cobalamin (cbl) from nutrient intake to its intestinal absorption. Endocytic receptors and proteins responsible for vitamin B12 intestinal absorption include cubilin (CUBN), amnionless (AMN), receptor-associated protein and megalin (LRP-2). The membrane megalin/transcobalamin II (TCII)-receptor complex allows the cellular uptake of cbl. Lysosomal-mediated degradation of TCII and subsequent release of free-cbl is essential for vitamin B12 metabolic functions. MS, methonine synthase; THF, tetrahydrofolate; MTHFR, methyltetrahydrofolate reductase; MCM, methylmalonyl CoA mutase.

RATIONALE FOR ORAL COBALAMIN TREATMENT

Two main reasons support the use of oral cobalamin treatment. First in elderly, the main causes of cobalamin deciency are pernicious anemia (2030%) and ` food-cobalamin malabsorption (5070%) (Andres, Goichot & Schlienger, 2000). Food-cobalamin malabsorption syndrome, which has only recently been identied, is a disorder characterized by the inability to release cobalamin from food or its binding proteins (Dawson, Gozzard & Lewis, 1988; Carmel, 1995). The partial nature of this form of malabsorption might produce a more slowly progressive depletion of cobalamin than does the more complete malabsorption engendered by disruption of intrinsic-factor-mediated ` absorption (Andres et al., 2005). This syndrome is usually caused by atrophic gastritis, related or unrelated to Helicobacter pylori infection, and long-term ingestion
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of antacids (Bellou et al., 1996) and biguanides (Sorich et al., 2008). In food-cobalamin malabsorption, the absorption of unbound cobalamin (free crystalline) is normal (Carmel, 1995). Second, between 1 and 5% of free cobalamin (or crystalline cobalamin) is absorbed along the entire intestine by passive diffusion. This absorption explains the mechanism underlying oral treatment of cobalamin deciencies (Lane & Rojas` Fernandez, 2002; Andres et al., 2004).

CLASSICAL TREATMENT OF COBALAMIN DEFICIENCY

The classical treatment for cobalamin deciency, particularly when the cause is not dietary deciency, is parenteral administration in most countries intramuscular injection of this vitamin (in the form of cyanocobalamin and, more rarely, hydroxy or methyl ` cobalamin) (Lane & Rojas-Fernandez, 2002; Andres

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`s Table 1. Stages of cobalamin metabolism and corresponding causes of cobalamin deciency (Andre et al., 2004) Stages and factors involved in cobalamin metabolism Ingestion of food Digestion, which involves haptocorrin, gastric secretions (HCl and pepsin), intrinsic factor, pancreatic and biliary secretions, and the enterohepatic cycle Absorption, which brings into play intrinsic factor and cubilin Transportation by transcobalamins Intracellular metabolism by various intracellular enzymes HCl, hydrochloric acid. Causes of cobalamin deciency Strict vegetarianism (patients who are sick in institutions or in psychiatric hospitals) Gastrectomy, pernicious anemia, food-cobalamin malabsorption Ileal resection, malabsorption, pernicious anemia, food-cobalamin malabsorption Congenital deciency in transcobalamin II Congenital deciency in various intracellular enzymes

Table 2. Hematological manifestations of vitamin B12 deciency in 201 patients with documented cobala` min deciency (Andres et al., 2007) Parameters Hemoglobin level (g/dl) MCV () Reticulocyte count (%) White cell count ( per mm3) Platelet count (103/mm3) Anemia with Hb level <12 g/dl Anemia with Hb level <6 g/dl Anemia and macrocytosis (MCV > 100 ) Isolated macrocytosis (MCV > 100 ) Microcytosis (MCV < 80 ) White cell count <4000/mm3 Neutrophil count <1000/mm3 Thrombopenia (<150 103/mm3) Neutrophil hypersegmentation Megaloblastosis Life-threatening manifestations Values 10.3 0.4 98.9 25.6 15.2 109/l 6200 4100 (4.915.1) (76142) (132) (50020 000)

146 42 (27580) 37% 2.5% 33.8% 17% 5% 14% 3% 10% 32% 60% 9%

France, the treatment involves the administration of 1000 lg of cyanocobalamin per day for 1 week, followed by 1000 lg/week for 1 month, followed by 1000 lg/month, normally for the rest of the patients ` life (Andres et al., 2004). In USA and UK, dosages ranging from 100 to 1000 lg/month (or every 23 months when hydroxocobalamin is given) are ` used during the rest of the patients life (Andres et al., 2007). Hydroxocobalamin may have several advantages because of a better tissue retention and storage (Hvas & Nexo, 2006).

ORAL COBALAMIN THERAPY

Generalities As cobalamin is absorbed by intrinsic factor-independent passive diffusion, daily high-dose (pharmacological dose) oral cyanocobalamin can induce and maintain remissions in patients with megaloblastic anemia (Elia, 1998; Lane & Rojas-Fernandez, 2002). In cases of cobalamin deciency other than those caused by nutritional deciency, alternative routes of cobalamin administration have been used in a curative perspective: oral (Lane & Rojas-Fernandez, 2002; Solomon, 2007) and nasal (Slot et al., 1997; Vidal-Alaball et al., 2005). These other routes of administration have been proposed to prevent discomfort, inconve` nience and cost of monthly injections (Andres et al., 2007). A recent review of Lane & Rojas-Fernandez (2002) has reported preliminary data of the usefulness of oral cobalamin treatment. It is notable that to date, oral cobalamin curative treatment accounts for more
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MCV, mean erythrocyte cell volume.

et al., 2004, 2007; Hvas & Nexo, 2006). However, traditions concerning both dose and schedule of adminis` tration vary considerably (Andres et al., 2005). In

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ORAL COBALAMIN THERAPY IN ADULT AND ELDERLY PATIENTS 5

than 70% of the total vitamin B12 prescribed in Sweden in 2000 (van Asselt et al., 1998). Historically, the Swedish team was the rst to routinely propose oral cobalamin therapy to cure vitamin B12 deciency. Prospective studies in determined population Our working group has developed an effective oral curative treatment in a well-determined population of patients with food-cobalamin malabsorption and pernicious anemia using crystalline cobalamin (cyanoco` balamin) (Berlin, Berlin & Brante, 1968; Andres et al., ` 2001, 2003; Kaltenbach et al., 2003; Andres et al., 2006). Our principal oral cobalamin treatment studies were open and not randomized (Table 3). All these studies use hematological parameters as principal and secondary end-points. Our data conrm the previously reported efcacy of oral crystalline cyanocobalamin, especially in food-cobalamin therapy ` (Berlin, Berlin & Brante, 1968; Andres et al., 2001, 2003; Kaltenbach et al., 2003). We observed that all orally treated patients corrected their vitamin B12 levels and at least two-thirds corrected their hematological abnormalities. Moreover, one-third of patients experienced a clinical improvement on oral treatment. In most cases of food-cobalamin malabsorption, low cobalamin doses (i.e. 1251000 lg of oral crystalline cyanocobalamin per day) were used. These results were also observed in a documented ` population of pernicious anemic patients (Andres et al., 2006). Randomized studies and cochrane review Findings are consistent with results of two prospective randomized controlled studies comparing oral cobalamin vs. intramuscular cobalamin therapy (Kuzminski ` et al., 1998; Andres et al., 2005). Kuzminski et al., in a prospective randomized trial including 38 patients, reported improvement of hematological parameters and cobalamin levels (mean value: 907 pg/ml), after 4 months of oral cobalamin therapy using a signicant ` higher dose (i.e. 2000 lg/day) (Andres et al., 2005). Bolaman et al., in a prospective randomized trial of 60 patients, also reported signicant improvement of hematological parameters and cobalamin levels (mean improvement: +140.9 pg/ml), after 3 months of daily 1000 lg of oral cyanocobalamin therapy (Kuzminski
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et al., 1998). An evidence-based analysis by the Vitamin B12 Cochrane Group supports the efcacy of oral cobalamin therapy in a curative objective, with a dose between 1000 and 2000 lg given initially daily and then weekly (Solomon, 2007). In this analysis, serum vitamin B12 levels increased signicantly in patients receiving oral vitamin B12 and both groups of patients (receiving oral and intramuscular treatment) had neurological improvement. The Cochrane group concludes that daily oral therapy may be as effective as intramuscular administration in obtaining short-term haematological and neurological responses in vitamin B12-decient patients. Nevertheless to our knowledge, the effect of oral cobalamin treatment in patients presenting severe neurological manifestations has not yet been adequately documented. Thus, meanwhile such an objective is eagerly awaited, parenteral cobalamin therapy remains recommended for these patients (Hvas & Nexo, 2006). In a randomized, parallel-group, double-blind, dose-nding trial, Eussen et al. showed that the lowest dose of oral cyanocobalamin required to normalize mild cobalamin deciency is more than 200 times the recommended dietary allowance of approximately 3 lg daily (i.e. >500 lg/day) (Bolaman et al., 2003). Limitations and clinical practice In clinical practice, the long-term efcacy of oral cobalamin therapy has not been validated yet in ` cobalamin-decient patients (Andres et al., 2004; Eussen et al., 2005). To date, as several authors suggest, oral cobalamin therapy remains one of medicines best kept secrets (Roth & Orija, 2004). As loading doses of cobalamin exceed by far physiologic requirements, clinical responses may result from pharmacologic effects on either cobalamin-related processes or on cellular functions completely unrelated to the known biochemical actions of cobalamin (Hvas & Nexo, 2006). As a result, blood cobalamin, methylmalonic acid and homocysteine values often fail to predict whether or not a patient will respond to cobalamin therapy (Solomon, 2005; Graham et al., 2007). Nevertheless, the following can be proposed: ongoing cobalamin supplementation until associated disorders are corrected (e.g. by halting the ingestion of the offending medication or exogenosis, or by treating H. pylori infection or pancreatic exocrine failure), then lifelong administration or, when applicable,

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Table 3. Prospective studies of oral cobalamin therapy in well-determined population of patients with cobalamin deciency Study population or type of B12 deciency Therapeutic modalities Results References (Berlin, Berlin & Brante, 1968) Oral crystalline cyanocobalamin: 650 lg/day, during at least 3 months Well-documented vitamin B12 deciency related to food-cobalamin malabsorption

Type of study

Number of patients

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Open prospective study

n = 10

Open prospective study

n = 20

Low vitamin B12 levels not related to pernicious anemia Well-documented vitamin B12 deciency related to food-cobalamin malabsorption Oral crystalline cyanocobalamin: 1000 lg/day, during at least 1 week Oral crystalline cyanocobalamin: between 1000 and 250 lg/day, during 1 month

Normalization of serum vitamin B12 levels in 80% of the patients Signicant increase of hemoglobin (Hb) levels (mean of 1.9 g/dl) and decrease of mean erythrocyte cell volume (ECV) (mean of 7.8 ) Improvement of clinical abnormalities in 20% of the patients No adverse effect Normalization of serum vitamin B12 levels in 85% of the patients No adverse effect

` (Andres et al., 2003)

ORAL COBALAMIN THERAPY IN ADULT AND ELDERLY PATIENTS

Open prospective study

n = 30

` (Andres et al., 2001)

Open prospective study

n = 30

Low vitamin B12 levels not related to pernicious anemia

Oral crystalline cyanocobalamin: between 1000 and 125 lg/day during at least 1 week Oral crystalline cyanocobalamin: 1000 lg/day, during at least 3 months

(Kaltenbach et al., 2003)

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Open prospective study

n = 10

Low vitamin B12 levels related to pernicious anemia

Normalization of serum vitamin B12 levels in 87% of the patients Signicant increase of Hb levels (mean of 0.6 g/dl) and decrease of ECV (mean of 3 ); normalization of Hb levels and ECV in 54% and 100% of the patients, respectively Dose effect effectiveness dose of vitamin B12 500 lg/day No adverse effect Normalization of serum vitamin B12 levels in all patients with at least a dose of vitamin 250 lg/day Dose effect effectiveness dose of vitamin B12 500 lg/day No adverse effect Signicant increase of serum vitamin B12 levels in 90% of the patients (mean of 117.4 pg/ml Signicant increase of Hb levels (mean of 2.45 g/dl) and decrease of ECV (mean of 10.4 ) Improvement of clinical abnormalities in 30% of the patients

` (Andres et al., 2006)

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ORAL COBALAMIN THERAPY IN ADULT AND ELDERLY PATIENTS 7

Parenteral administration:
(regardless of the etiology of the vitamin deficiency)

Attack treatment: Cyanocobalamin: 1000 g per day for one week, then 1000 g per week for one month

Maintenance treatment: Cyanocobalamin: 1000 g per month until the cause is corrected, or for life in the case of pernicious anemia

Oral administration:
(for intake deficiency, food-cobalamin malabsorption and pernicious anemia)

Attack treatment: Cyanocobalamin: 1000 g per day for one month

Figure 2. Therapeutic protocols proposed by the university hospital of Strasbourg, France.

Maintenance treatment: Cyanocobalamin 125 to 500 g per day for intake deficiency and food-cobalamin malabsorption and Cyanocobalamin: 1000 g per day for pernicious anemia

sequential administration (Lane & Rojas-Fernandez, ` 2002; Andres et al., 2007). Our therapeutic protocols are outlined in Figure 2 (Lane & Rojas-Fernandez, ` 2002; Andres et al., 2004, 2007). We suggest a dose of 1000 lg of oral cyanocobalamin for pernicious anemia for life, and a mean daily dose of 250 lg for foodcobalamin malabsorption until the cause of foodcobalamin malabsorption is cured.

hematological manifestations related to cobalamin deciency. Although, signicant advances have been made in the treatment of cobalamin deciency, other studies are still required to test whether oral cobalamin therapy is suitable in cobalamin-decient patients displaying severe neurological defects; and if so determine the effective dose necessary for a balanced vitamin B12 homeostasis in these patients.

CONCLUDING REMARKS
This review conrms the previously reported efcacy of oral cobalamin treatment in adults and elderly patients. The literature has demonstrated that oral cobalamin therapy is safe, effective and alleviates some of the drawbacks associated with parenteral cobalamin therapy. The recommendation that can be drawn from our clinical practice experience and that of others is a daily oral cyanocobalamin administration at a dose of 2502000 lg for the treatment of

ACKNOWLEDGEMENTS
We are indebted to Professor Marc Imler and JeanLouis Schlienger who initiated this work. The research on cobalamin deciency was supported by a grant of the Fondation de France (Prix Robert et Jacqueline Zittoun 2004).

COMPETING INTERESTS
No author has any conict of interest.

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